Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are very common and devastating disorders of aging. The primary causes for sporadic AD and PD are unknown. It is now established that both AD and PD involve a systemic bioenergetic defect caused by specific lesions in the mitochondrial electron transport chain. The defects are primary (genetic), arising from mitochondrial DNA (mtDNA) and can be transferred from cell to cell through transfer of mtDNA. Transfer of mtDNA from AD or PD patient platelets into mtDNA-depleted human SY5Y neuroblastoma cells results in the creation of a model "neuron" in which genetic, biochemical, and cellular features of the AD and PD phenotypes can be studied. This program consists of four projects. These projects will use this novel method to characterize further the mitochondrial genetic abnormalities in AD and PD mtDNA, to quantitate intracellular mitochondrial turnover and "trafficking" of both normal and impaired mitochondria, to study the role of mitochondrial failure in neurodegeneration, the relationships between oxygen radicals and apoptosis in neurodegeneration, the effects of mitochondrial abnormalities on neuronal calcium metabolism, and the molecular mechanisms of neurotrophin action and control of cell death pathways. This program will further characterize involvement of the mitochondrial genome in both AD and PD and will strengthen a hypothesis about the primary pathogenic factor in each disorder-a hypothesis which can be directly tested through sequencing of mtDNA. Establishment of primary involvement of mtDNA in AD and PD will also provide new therapeutic opportunities aimed at modifying dysfunction or dealing with consequences such as oxygen radical production. This program will also develop an excellent model system for investigation of therapeutic maneuvers. The four Projects will be supported by a Molecular Biochemical and Anatomical Cell Culture Core Laboratory and an Administrative Core. The Program will receive regular oversight by an Internal Advisory Committee and through use of three external consultants per year.